Recent evidence appreciating the contribution of stromal cell heterogeneity in pathophysiology emerges as a new opportunity to stratify arthritic diseases and develop more targeted clinical tools. The project group postulates that different synovial fibroblast (SF) profiles determine the nature of Synovial MicroEnvironment (SME), and fuel the development of different types of arthritic diseases by exhibiting differential sensitivity to inflammatory stimuli. The ensuing transcriptional responses dictate the changes in the cellular composition of the diseased SMEs, characterizing the distinct pathological and clinical findings in each arthritic phenotype. Consistent with the hypothesis, the group aims to explore the stromal-mediated causalities in Psoriatic Arthritis (PsA) and delineate the PsA-specific SF profile. With the integrative transcriptomic and functional analyses, the group aspires to assist the generation of the distinct stromal codes governing arthritic diseases.
To address the project's hypothesis, the group will follow a human/mouse integrative analysis, combining the high-resolution analysis of PsA-affected synovia with molecular and functional analysis on the pathogenic contribution of the SFs ex vivo and in modeled PsA. With this analysis the aim is to:
Milestone I: The PsA synovium at single cell level
Milestone II: The stromal codes of inflammatory arthritides
Milestone III: Pathogenic mechanisms in modelled PsA: focusing on stromal compartment
Milestone IV: Delivery of A20-ZnF7 protein domain as a therapy to suppress PsA
The expected results will inform healthcare innovation and benefit the patients by providing targeted biomarkers for segregating inflammatory arthritides, and testing novel therapeutics. Moreover, the high-resolution analysis will be deposited in public databases, serving as a key resource for the formation and validation of additional mechanistic hypotheses.